Abstract

We have previously reported that in a mouse model of allergic sensitization, low level inhaled LPS (LPSlow) signaling through TLR4 was necessary to induce Th2 responses while high level LPS (LPShigh) induced Th1 responses to inhaled antigen. The mechanism by which LPS signaling resulted in Th2 sensitization involved the activation of antigen-containing dendritic cells (DC). It remains unclear whether induction of these responses is dependent on TLR signaling in DCs, other lung cells, or in both. Here we report that antigen/LPShigh sensitized chimeric mice specifically lacking TLR4 signaling in the hematopoietic compartment (HPC) but sufficient for TLR4 in the stromal compartment (SC+HPC-) do not mount Th1 responses following antigen challenge while SC-HPC+ mice do. Strikingly, however, SC+HPC- mice mount exaggerated Th2 responses. Stromal TLR4 signaling in SC+HPC- mice leads to upregulation of the Th2-inducing Notch ligand Jagged-1 in DCs but not the Th1-inducing ligand Delta-4. In coculture, DCs activated by the stromal response to LPS polarize naïve antigen specific CD4 T cells to produce Th2 cytokines. These studies demonstrate that the TLR4-mediated response of stromal cells, through conditioning of DCs, is sufficient to induce robust allergic inflammatory responses to inhaled antigen containing LPS and define a novel role for lung stromal cells in the TLR4-dependent induction of allergic Th2 responses.